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Fluid Management for Sepsis
17 Plays3 years ago
In this episode of the podcast, we will discuss Fluid Management for Sepsis through the lens of the recently published CLOVERS clinical trial. Our guest is Dr. Nathan Shapiro, Professor of Emergency Medicine at Harvard Medical School, and an attending physician in the Department of Emergency Medicine at Beth Israel Deaconess Medical Center. Dr. Shapiro is the Vice Chairman of Research for the Emergency Department. Dr. Shapiro is a lead author and investigator for the recently published CLOVERS clinical trial.
Additional Resources
Early Restrictive or Liberal Fluid Management for Sepsis-Induced Hypotension. CLOVERS clinical trial: https://www.nejm.org/doi/full/10.1056/NEJMoa2212663
Restriction of Intravenous Fluids in ICU Patients with Septic Shock. CLASSIC clinical trial: https://www.nejm.org/doi/full/10.1056/NEJMoa2202707
Surviving Sepsis Campaign: Guidelines 2021: https://www.sccm.org/Surviving-Sepsis-Guidelines-2021
Early Goal-Directed Therapy in the Treatment of Severe Sepsis and Septic Shock: https://www.nejm.org/doi/full/10.1056/nejmoa010307
Early, Goal-Directed Therapy for Septic Shock: Metanalysis of the ARISE, ProCESS, and PriMISe clinical trials: https://www.nejm.org/doi/10.1056/nejmoa1701380
Books Mentioned in this Episode:
Extreme Ownership: How Navy SEALs Lead and Win. By Jocko Willink and Leif Babin: https://bit.ly/3Ktadmk
Recommended
Transcript
Introduction to Critical Matters Podcast
00:00:06
Speaker
Welcome to Critical Matters, a sound podcast covering a broad range of topics related to the practice of intensive care medicine.
00:00:14
Speaker
Sound provides comprehensive critical care programs to hospitals across the country.
00:00:19
Speaker
To learn more about our programs and career opportunities, visit www.soundphysicians.com.
00:00:26
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And now your host, Dr. Sergio Zanotti.
Fluid Resuscitation in Sepsis: Past and Present
00:00:33
Speaker
Intravenous fluid resuscitation is a common therapeutic intervention in patients with sepsis-induced hypotension and septic shock.
00:00:39
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For years, early and aggressive fluid resuscitation has been advocated without high levels of evidence to guide clinicians.
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Over the last several years, concerns for potential harm with overly aggressive fluid therapy have been raised by experts based on observation and retrospective studies.
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In today's episode of the podcast, we will discuss fluid management for sepsis-induced hypotension through the lens of the recently published Clovers clinical trial.
00:01:04
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Our guest is Dr. Nathan Shapiro.
00:01:06
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Dr. Shapiro is a professor of emergency medicine at Harvard Medical School and an attending physician in the Department of Emergency Medicine at Beth Israel Deaconess Medical Center in Boston.
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Dr. Shapiro is the vice chairman of research for the emergency department.
00:01:19
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He is a renowned clinician, educator, and researcher with over 200 peer-reviewed publications.
00:01:24
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His research interests include sepsis, translational research, and the overlap of critical illness between emergency medicine and critical care.
00:01:31
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Dr. Shapiro is a lead author and investigator for the recently published Clover's clinical trial.
00:01:36
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Nate, welcome to Critical Matters.
00:01:39
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Great.
00:01:39
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Thanks for having me.
Historical Perspectives on Sepsis Treatment
00:01:41
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So I think that we both grew up in the era of a lot of fluid and early, and obviously a lot of that was triggered through the Rivers trial.
00:01:50
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And I still remember being taught that edema and some of the other consequences of overly aggressive flu recitation were
00:02:00
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We're just cosmetic and kind of like, that's the price we pay to save these patients.
00:02:04
Speaker
But over the years, obviously, that pendulum has kind of moved.
00:02:09
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And we now are having finally some high-level clinical trials published in the last couple of years that are trying to maybe give us a little bit more evidence in terms of delucidating this very complicated issue of fluids.
00:02:25
Speaker
which is something we do every day yet don't really know how to do very well, it seems, yet.
00:02:30
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So could you start maybe, Nate, giving us a little bit of a perspective, an overview of how we got from Rivers to the famous or infamous 20 ml, 30 ml kg bolus to where we are today and setting the stage for why you and your co-investigators thought about moving forward with the Clovers clinical trial?
00:02:49
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Sure, I'd be happy to.
00:02:50
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So I'll take us actually back a little bit before Rivers.
00:02:54
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So before 2001 Rivers, when you had patients with sepsis, a lot of times patients were maybe not attended to so quickly.
00:03:05
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Maybe there wasn't compulsive fluid resuscitation and there was a little bit of unintentional neglect.
00:03:12
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And when Rivers came, I think it did two things.
00:03:15
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One is it really threw down the gauntlet to say, look, if we pay attention to these patients and resuscitate them better, there's an opportunity to realize morbidity and mortality benefit.
00:03:27
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We can do something that's going to make a difference.
00:03:29
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And if we act early, we can do something that's going to make a difference downstream.
00:03:35
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And with the Rivers trial, it was really, if you think about it, it was a structured approach to performing a careful resuscitation.
00:03:45
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It was a structured approach to look at endpoints for your fluids or your vasopressors, and if those endpoints aren't being met, to escalate your therapy.
00:03:54
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And so that forced us also to give more fluids.
00:03:59
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One thing that happened, one observation from Peter Rosen, who's kind of one of these forefather of emergency medicine in many ways, when he looked at Rivers, he just said, look, one thing it's doing is it's giving, doctors are good at treating numbers.
00:04:13
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So when you say make a patient volume replete, that's hard for them.
00:04:18
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When you say put in the CVP and make that number between eight to 12, doctors know how to do that.
00:04:24
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And so Rivers really forced us to give a compulsive resuscitation.
00:04:30
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Then what happened though was, you know, I think the Rivers trial gets a lot of credit with changing the mindset of physicians and the mindset then shifted.
00:04:41
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to let sepsis identification is important.
00:04:45
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And it's also where the Surviving Sepsis campaign came in, which is just general sepsis awareness.
00:04:50
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Resuscitating patients with sepsis is important.
00:04:53
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Getting to them early is important.
00:04:54
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And the mindset of clinicians changed.
00:04:57
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And my interpretation is it changed so much that
Current Debates in Septic Shock Management
00:05:00
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when Process, Promise, and Arise were performed, there was a mindset shift.
00:05:06
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under-resuscitated control groups from the era kind of pre-rivers or peri-rivers, those had gone away to the point that we didn't necessarily need a rigid protocol in order to do a good resuscitation.
00:05:19
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So let me pause there.
00:05:22
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I know it's a bit of a monologue.
00:05:24
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No, I think that's perfect.
00:05:26
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And I think you bring up a very important point that is interesting
00:05:31
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directly relevant to what we're talking about, but I think also translates into many discussions in critical care and in medicine in general, which is the importance of context, right?
00:05:43
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A lot of people look at the RIVER study from a point of view of what we know today, and it's easy to say this, say that, but you are absolutely correct at the time when it came out in the early 2000s,
00:05:57
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Patients were not being treated aggressively, were not being recognized.
00:06:01
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And probably, like you said, there was a level of neglect that probably impacted outcomes.
00:06:08
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And changing that mind shift, I think, was perhaps the greatest value of the Rivers trial, which I'm pretty sure, till this day, is probably, if not, one of the most quoted and referenced studies in critical care.
00:06:23
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But like you said, I mean, it just kind of...
00:06:26
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put a very bright light on a very important population of patients and there was something that we could do about that.
00:06:33
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And I think that that is something that is not discussed enough, especially people who may have not been in practice back in that time.
00:06:41
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And it's very important and it really informs everything we do.
00:06:44
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And I think the same thing happens as we'll dive in deeper into some of the clinical trials that you've conducted.
00:06:50
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that you plan the study, right?
00:06:53
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And by the time it's completed, things have changed, right?
00:06:55
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Or a lot of things have occurred.
00:06:57
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But I think it's a very important point.
00:07:01
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Could you comment a little bit on how we went from giving, I think early was definitely, I mean, I don't think anybody disagrees with early goal-directed therapy, right?
00:07:12
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With the concept.
00:07:13
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I mean, the question that now we're trying to figure out is what should be the goals, right?
00:07:17
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And I think that is where we struggled the most.
00:07:20
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And like you said, when promise arise and now these other clinical trials came around, the wild type was already drastically different than what we had before.
00:07:30
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Now, in terms of your perspective, Nate, could you comment a little bit about this whole idea of being more conservative or restrictive with fluid versus deliberate administration and how we start thinking about this as a potential target for our visitation?
00:07:50
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Sure.
00:07:50
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So, you know, in general, as you mentioned, the pendulum, it's been a swinging pendulum over the last really 20 years.
00:07:58
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So there's pre-rivers where we're probably under-resuscitating and then post-rivers where there's concerns for over-resuscitation.
00:08:06
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And there's a lot of discussion about that.
00:08:09
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And so then the idea rose and there's a lot of observational studies out there that showed associations between the amount of fluids given or the fluid balance and adverse outcomes.
00:08:20
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The only problem is there's also a lot of confounding in these observational studies.
00:08:24
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In other words, patients who are doing really well, you'll leave them alone.
00:08:29
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They're doing well.
00:08:30
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Patients who are hypotensive or have a rising lactate who clinically look worse, typically will do something.
00:08:38
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And one of the things we can do is add more fluids.
00:08:41
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So it's possible that at the end
00:08:43
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of the day, there is this observation, but there's also a big bias by, there's a big bias by indication.
00:08:52
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In other words, the confounding or confounding by indication, whereas patients who are doing worse are getting more fluids because you're trying to chase their blood pressure.
00:09:00
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And so it could be that fluids are just a really good biomarker for a sick patient.
00:09:05
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But those are the kinds of studies that have fueled the discussion that maybe we're over-resuscitating.
Evidence and Opinion in Fluid Management
00:09:12
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And it's a valid question, a valid discussion.
00:09:15
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And the irony of this swinging pendulum between a lot of fluids and the little fluids, conservative versus liberal fluid management, is that a lot of that discussion has occurred in the absence of data.
00:09:27
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And while that's typically what happens, right, if you have a clean study with a clear outcome,
00:09:32
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argument, it's when there's a lack of data that it tends to be more opinionated.
00:09:36
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And I think that's what happened here.
00:09:39
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So we obviously now in the last couple of years have had a couple of randomized studies that have been proposed.
00:09:49
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Two have been completed, the Classic and the Clovers, which is the study you've been involved in, which we'll talk about into detail.
00:09:57
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And my understanding is that there's another large study ongoing right now that is looking at the similar issue.
00:10:03
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Is that correct?
00:10:04
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That's correct.
00:10:05
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Well, we should also throw in the
00:10:07
Speaker
not throw in, but we should also mention the trials out of sub-Saharan Africa where, you know, they're different, they're different populations, but still, you know, there's still the principle of liberal versus restrictive fluid resuscitation in a randomized way and restrictive, um, seem to carry the day in those trials.
00:10:27
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I think that how that translates to other diseases out of the pediatric population per se, um,
00:10:36
Speaker
is unknown, but it still gives pause to the physiology to say in one population restrictive was better.
00:10:42
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So I think that also fuels the discussion.
00:10:45
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But then we had classic and the big difference between classic and Clovers, I'm sure we'll get into it a little more is classic starts a bit later.
00:10:53
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So classic is recruits out of the ICU, whereas Clovers recruits earlier, but still with classic, we saw good separation between the approaches and we saw no difference in outcomes.
00:11:06
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Okay, so, and just to refresh our audience memory, the Sub-Saharan studies you referred to were in pediatric kids, mostly sick with malaria.
00:11:17
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And that was, I think, an important finding because the presumption was that fluids are not that harmful, that if anything, they're gonna have a great impact, and that we're gonna save a whole bunch of kids by giving them just fluid.
00:11:30
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And lo and behold, like you said, fluids actually killed more kids.
00:11:34
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probably from pulmonary edema and other complications than the ones who got restrictive fluids.
00:11:38
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So like you said, it causes
Examining the Clovers Clinical Trial
00:11:40
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us some pause and maybe what we thought was straightforward is a little bit more complicated.
00:11:46
Speaker
So let's dive into clovers, which is really, I mean, obviously what we want to talk about today.
00:11:52
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And then through the lens of clovers, also want to hear a little bit more about your perspective as a clinician and
00:12:00
Speaker
and where you stand today.
00:12:01
Speaker
So why don't we start with the name?
00:12:04
Speaker
I always find it interesting with the name.
00:12:08
Speaker
And could you tell us what Clover stands for?
00:12:11
Speaker
So it's crystalline liberal or vasopressor early resuscitation in sepsis.
00:12:18
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And we had some, you know, any good study needs a good acronym, but we also have clear ethical guidelines that we do not cheat.
00:12:28
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We don't do the thing where you use the second letter capitalized.
00:12:32
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So this is true first letter.
00:12:35
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The credit goes, the final credit goes to Dick Indy and his family, because evidently it's a family affair between him and his kids to come up with the right acronym.
00:12:44
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So he nailed it.
00:12:46
Speaker
It also, this is, um, the studies conducted by the pedal network sponsored by NHLBI.
00:12:51
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And the theme is the theme of pedal is that, uh, all studies have to be plant related.
00:12:59
Speaker
So, so it had to be a plant or flower related study.
00:13:04
Speaker
Cool.
00:13:05
Speaker
There you go.
00:13:05
Speaker
I mean, I always wonder what are the backdoor discussions on the names, but you're right.
00:13:11
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It follows all the rules in terms that it is a plant.
00:13:15
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It only uses the first letter of the words in the acronym.
00:13:20
Speaker
But more importantly, I think it's a good description of what you were trying to do.
00:13:24
Speaker
So why don't you tell us about the hypothesis and what you were really trying to demonstrate or study here?
00:13:31
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Yeah, so the real study is, so it's really comparing a fluid-minded approach versus vasopressor-minded approach.
00:13:39
Speaker
And it was, um, initially we said, we want to know a lot of fluids versus the little fluids.
00:13:46
Speaker
But then as we were discussing this from a clinical perspective and Todd writes, um, from Vanderbilt gets the credit for really, um, really making the description in a very clear and concise way, which is it's really fluids first with vasopressors later versus vasopressors early in the course with fluids later after the initial resuscitation.
00:14:09
Speaker
So we felt that patients were going to get that initial roughly 20 CC to 30 CC kg.
00:14:15
Speaker
It was roughly, or, you know, when they hit the door, pre-hospital, et cetera.
00:14:20
Speaker
So we said, let's acknowledge that you're going to get initial bolus of fluids.
00:14:24
Speaker
And if that fixes you, then we're done.
00:14:26
Speaker
But if it doesn't fix you, then we want to know, should we reach for more fluids and keep reaching for fluids and then go to vasopressors?
00:14:34
Speaker
In other words, fill up the tank before going to vasopressors, or is it okay to,
00:14:39
Speaker
do vasopressors right away.
00:14:42
Speaker
And that's really, we're trying to compare those two groups.
00:14:45
Speaker
And more importantly, we really tried to find a balance and we'll get into this a little bit more between a pragmatic trial, um, an efficacy trial versus an effectiveness trial.
00:14:56
Speaker
In other words, we were really trying to say, if I'm a physician at the bedside of a patient and I'm going to take a liberal approach, how would I resuscitate the patient?
00:15:07
Speaker
And so we then created a protocol so we could reproduce our approach and describe what we did.
00:15:12
Speaker
But the idea is I'm a physician at the bedside.
00:15:15
Speaker
What am I going to do if I'm a liberal minded physician?
00:15:18
Speaker
And then on the other side of the coin, I'm a restrictive minded physician or conservative fluid management minded physician.
00:15:26
Speaker
I really think fluids are bad and I'm going to go to vasopressors early.
00:15:29
Speaker
How would I treat
Fluid and Vasopressor Strategies in Sepsis
00:15:30
Speaker
my patient?
00:15:31
Speaker
And so we wrote two protocols kind of to really try and
00:15:35
Speaker
reproduce or characterize those personas in resuscitating patients.
00:15:40
Speaker
Absolutely.
00:15:41
Speaker
And before we move forward, just for benefit of our audience, pragmatic trials are something that 10 years ago I rarely encounter.
00:15:51
Speaker
I don't even think I can remember people talking about that.
00:15:55
Speaker
But especially with COVID and before COVID as well, but I think it's accelerated.
00:16:01
Speaker
And more and more, we read about pragmatic trials and critical care specifically.
00:16:07
Speaker
Could you just tell us what do you understand or how do you define pragmatic trial?
00:16:13
Speaker
So pragmatic is something where there's really little interference from the study teams.
00:16:18
Speaker
And a pure pragmatic trial here would have been essentially to randomize patients to a liberal group and then just to hand a note to the clinicians that say, please use a liberal approach and then let it run versus one that says, please use a restrictive approach and let it run.
00:16:36
Speaker
Now, if we did that, we were worried that we wouldn't really test the hypothesis we were seeking to test.
00:16:43
Speaker
So what we did was we created clinical protocols that give more specific suggestions.
00:16:50
Speaker
It's instructions slash suggestions for each of those approaches.
00:16:54
Speaker
But I also want to underscore that in that, we also wanted to acknowledge that there would be some important clinical judgment that would need to be involved in any bedside care.
00:17:04
Speaker
And so one of the instructions per se was if there's something that the clinical team feels is in the best interest of the patient, then they should do it.
00:17:15
Speaker
And so it was use a restrictive approach, but if something comes up or something arises where you think you need to override this protocol and just do give fluids to the patient, then you're allowed to do it.
00:17:28
Speaker
And so we really tried to find the balance between this, let's just let it run in the way
00:17:35
Speaker
let's just let it run and just see how it works out in clinical practice by just saying please do restrictive and please do liberal versus some rigid criteria that can't be broken.
00:17:45
Speaker
And so that's why we're, we described it or thought of it really as a, as a hybrid tagmatic or hybrid effective efficacy versus effectiveness trial.
00:17:56
Speaker
Perfect.
00:17:57
Speaker
And I think that just to emphasize a point you made, which I think is super important for this topic, is that really when we talk about hemodynamic support and sepsis-induced hypotension, septic shock,
00:18:10
Speaker
it's the combination and the sequence, right, or the timing of fluids and vasopressors.
00:18:16
Speaker
Usually that is difficult.
00:18:18
Speaker
And like you said, I mean, this is not only a fluid trial because what a lot of people will do in these patients is keep giving fluid with the idea of delaying or minimizing the use of vasopressors.
00:18:30
Speaker
And if you just look at the vasopressor story,
00:18:33
Speaker
There's also a pendulum, right?
00:18:35
Speaker
And pre-rivers, a lot of people would argue that because these patients got no fluid, using vasopressors in them might have been harmful for the kidneys and for other organs.
00:18:46
Speaker
So I think it's finding that balance, right?
00:18:48
Speaker
The timing of and the combination of.
00:18:51
Speaker
And really, I think in practice, a lot of people just keep giving fluid as a vasopressor sparing kind of technique, let's call it.
00:19:01
Speaker
Agreed.
00:19:02
Speaker
And I'd also like to highlight that the inclusion criteria for our trial were actually blood pressure less than a hundred after initial minimum of one liter fluids, a systolic of less than a hundred.
00:19:14
Speaker
And that was very deliberate because we felt that there was a group of patients in the traditional, you know, above 90 in the traditional shock definition,
00:19:26
Speaker
but below a hundred where they're still reasonably relatively hypotensive, where the practice is let's give them a lot of fluids.
00:19:33
Speaker
So their systolic doesn't dip below 90 at which point we'll feel compelled to get these oppressors.
00:19:40
Speaker
So since patients hovering in the nineties end up getting a lot of fluids, um, in order to keep them from that 90 ICU mandatory kind of zone, we felt that it's important to know whether that practice,
00:19:53
Speaker
is actually harmful so for the patients in 90 to 100 what we were actually testing in the restrictive group was just stopping right just just sit on your hands don't worry let someone be in the 90s and watch them yeah perfect and uh to remind everybody the hypothesis was that the restrictive basal pressure early would would be associated with a better outcome correct
00:20:21
Speaker
Correct.
00:20:22
Speaker
And it was a 90-day mortality prior to discharge.
00:20:27
Speaker
Can you explain the primary outcome in more detail?
00:20:30
Speaker
So I think that some people, I've just discussed the trial, and it seems that some people got a little bit confused because it's a patient-relevant outcome, obviously, but there are certain rules, like what happens if you get discharged or didn't get discharged by 90 days, and how was it applied?
00:20:51
Speaker
Sure.
00:20:51
Speaker
So it's a little bit of a, it's an outcome that we've been using as part of the pedal network and actually it's predecessor arts net for some time.
00:21:00
Speaker
But the idea is if you're discharged from the hospital and you go back to the, the circumstance from where you came, that's considered
Outcomes and Implications of the Clovers Trial
00:21:10
Speaker
the end point.
00:21:11
Speaker
So if you come from home, you're admitted to the hospital and you're discharged before night before 90 days, and that's to your
00:21:21
Speaker
for the analysis and the end point in the positive directions reached.
00:21:27
Speaker
Now, if you come from home and you're in the hospital and you get discharged to hospice and pass away, then you've never made it home.
00:21:36
Speaker
So you've been discharged from the hospital, but you've gone to, say, hospice and you've never made it home.
00:21:40
Speaker
If you get discharged, and so there would be a negative outcome.
00:21:44
Speaker
If you get discharged from the hospital and you go to the nursing home and you pass away at the nursing home, also a negative outcome.
00:21:52
Speaker
If you get this from the hospital and you go to the nursing home and then go back to home, then it's considered a positive.
00:21:59
Speaker
And same if you get this, if you live in a nursing home, come to the hospital and go back to the nursing home, also considered a final conclusion is a positive outcome.
00:22:09
Speaker
Perfect.
00:22:10
Speaker
And in terms of the trial design, any comments you want to add before we move forward?
00:22:17
Speaker
I think it's really, it was really that we tried to simplify it to,
00:22:22
Speaker
You come to the hospital, you meet criteria if it's within four hours.
00:22:27
Speaker
So I think the within four hours part is really critical.
00:22:30
Speaker
So four hours from eligibility to enrollment was the eligibility window.
00:22:36
Speaker
On average, patients were randomized within an hour of meeting criteria.
00:22:42
Speaker
So we got the patients early.
00:22:45
Speaker
And that, as you pointed out, is a big difference with the classic trial that your patients almost exclusively came through the ED and early.
00:22:53
Speaker
And in the classic trial, you had patients coming from the floor, patients who came from the OR, not necessarily the same kind of timeframe of their clinical care.
00:23:04
Speaker
Correct.
00:23:05
Speaker
You know, in unbalanced, they got the in classic patients were enrolled fairly early in the course, but it's definitely a discrepancy in trial.
00:23:14
Speaker
I think we were about 92 or 93% of patients from the emergency department and they had about 30 patients or so coming from the floor and some coming from the operating.
00:23:24
Speaker
Perfect.
00:23:25
Speaker
You mentioned the patient population, some of the inclusion criteria, any relevant exclusion criteria you want to share?
00:23:34
Speaker
I mean, at the end of the day, it was, could a patient be reasonably randomized to either arm?
00:23:41
Speaker
So if patients had, say, DKA and were severely volume deplete, then they can't really as well be randomized to restrictive.
00:23:50
Speaker
Or if a patient comes in in a state of fluid overload, then...
00:23:55
Speaker
you're not really, it wouldn't make sense to randomize them to the liberal group where they're not going to get more fluid.
00:24:01
Speaker
And so it had to be a patient where there's equipoise based on the available data on which direction they could go.
00:24:08
Speaker
And then if there's equipoise and the clinician says, okay, I'm willing to do both.
00:24:12
Speaker
Because the other thing we didn't want to do was randomize a patient to the liberal group and then have somebody say, I don't think patients should ever, ever.
00:24:21
Speaker
And so if there was equipoise on the patient in that zone, then essentially they were eligible to be enrolled and the criteria were really structured around realizing that equipoise.
00:24:34
Speaker
So if a patient had already received over three liters of fluids, they wouldn't be enrolled because they're already towards the
00:24:40
Speaker
Perfect.
00:24:41
Speaker
So let's talk about the trial intervention and what really happened.
00:24:45
Speaker
So the patient met criteria.
00:24:48
Speaker
It was early on.
00:24:49
Speaker
They usually, like you said, would have gotten their initial bolus.
00:24:53
Speaker
They still had blood pressure issues.
00:24:55
Speaker
They would be enrolled.
00:24:56
Speaker
And what happened and for how long at that point?
00:24:59
Speaker
So if they go to the liberal group, then the first thing that happens and they're randomized to the liberal group,
00:25:06
Speaker
The first thing that happens is you titrate vasopressors down if you can, if it's safe.
00:25:14
Speaker
And then you give what is going to be ultimately a two-liter infusion.
00:25:19
Speaker
And
Applying Research to Clinical Practice
00:25:20
Speaker
you can, at the one-liter mark, you would stop, assess the patient.
00:25:24
Speaker
If their volume replete and their vital signs have normalized, then you don't
00:25:28
Speaker
need to continue the rest of the second leader that's at the discretion of the physician but if they're not volume replete by clinical assessment and or the vital signs aren't normalized and we put parameters around that they continue it out so in the liberal group essentially most patients got about initial two leaders and then from there there's the criteria to give fluids which if you look at it we just find something we gave some suggestions like heart rate or lactate etc but
00:25:58
Speaker
So if any reason at the bedside, a clinician thinks the patient needs more fluids, then the instruction is to give more fluids.
00:26:06
Speaker
If any measured reason, and we didn't want to make this a device trial.
00:26:09
Speaker
So we had,
00:26:10
Speaker
considered using non-invasive human dynamic monitoring or considered using echo, et cetera.
00:26:18
Speaker
But we kind of wanted to try and keep this as simple and most as generalizable as possible.
00:26:24
Speaker
And so we, we essentially said you can use whatever you want.
00:26:29
Speaker
If you think a patient
Recommended Reading and Closing Thoughts
00:26:30
Speaker
needs more fluid, give them more fluid.
00:26:32
Speaker
And we also did provide some general guidance around if you are going to do non-invasive hemodynamic monitoring or echo about fluid responsiveness, et cetera, but it was just general guidance.
00:26:44
Speaker
It wasn't mandated in the trial.
00:26:45
Speaker
And the truth is at the end of the day, we asked about it and it seems that there was very little kind of more advanced monitoring used to guide these
00:26:55
Speaker
Then in the fluid, we also gave, we called them rescue criteria, which is if you think that you need to cross over from fluids to use vasopressors, we can have some general guidance around
00:27:18
Speaker
of 50 and you feel like you need to hang some vasopressors that was allowable if after you've given five liters of fluids in total you want to go to vasopressors you could do that at any time because we felt like after five liters we realized there's a liberal fluid resuscitation if you're lactate um
00:27:37
Speaker
was elevated and rising.
00:27:38
Speaker
That was another reason to cross over.
00:27:40
Speaker
So we tried to give general indications to give fluid, which was really at the end of the day, just about anything you wanted to do clinically.
00:27:46
Speaker
And then cross rescue criteria for if you want to go to vasopressors before it was that arm of the trial was complete.
00:27:56
Speaker
Perfect.
00:27:57
Speaker
And the other arm?
00:27:59
Speaker
Yeah.
00:28:00
Speaker
And then restrictive.
00:28:01
Speaker
So the first thing we do is stop fluids.
00:28:03
Speaker
There was a provision.
00:28:04
Speaker
There was some
00:28:06
Speaker
concern about whether
00:28:09
Speaker
all patients need to have that 20cc per kg bolus, 20 to 30cc per kg bolus.
00:28:14
Speaker
And we weren't testing that in particular.
00:28:17
Speaker
It was kind of part of it.
00:28:18
Speaker
So we said any patient in restrictive can have up to two liters of fluids for whatever reason.
00:28:22
Speaker
But after that, we just essentially, if the patient's hypotensive, you'd have vasopressors.
00:28:29
Speaker
If you got to high doses of vasopressors, that was some of the indication for rescue fluids.
00:28:34
Speaker
If there was any sign of peripheral ischemia, if the lactate was elevated,
00:28:40
Speaker
So in general, it was try not to use fluids unless you really need to need to cross over.
00:28:46
Speaker
Perfect.
00:28:48
Speaker
Go ahead.
00:28:49
Speaker
Go ahead.
00:28:49
Speaker
Sorry, Nick.
00:28:50
Speaker
Go ahead.
00:28:51
Speaker
One other element that wasn't really a randomized element of the trial, but I think it was an important highlight was
00:28:58
Speaker
When we were, and just for perspective, the way the trial was created was we had the Clovers Committee, which was a group of maybe 15 or 20 emergency physicians, critical care physicians, surgeons, some nurses, and we put our heads together and said, let's, from a clinical perspective, really design these arms.
00:29:20
Speaker
One of the big discussion points that came up was the use of peripheral vasopressors.
00:29:24
Speaker
And there was, when we were having these discussions, there was a lot of physicians and institutions who were using some peripheral vasopressors, whereas other institutions, they weren't.
00:29:35
Speaker
They almost thought it was taboo.
00:29:37
Speaker
And there was protocols against it.
00:29:39
Speaker
And so we felt that this was
00:29:41
Speaker
There was really a growing experience with the use.
00:29:45
Speaker
People in general, their experience was that it was safe.
00:29:48
Speaker
And we also felt that if we want to facilitate early vasopressors, this was a way to do it.
00:29:53
Speaker
Put a peripheral IV and start your vasopressors and then switch over to central line at some point if it looks like it's going to be persistent.
00:30:01
Speaker
And so we wrote the use of peripheral vasopressors into the trial where it was a protocol specified allowable action.
00:30:11
Speaker
And we also put it into the consent.
00:30:14
Speaker
So that way, if there was institutions where they typically didn't use peripheral vasopressors, it was consented for, from the patient perspective, the clinician had to approve it and it was an allowable action.
00:30:28
Speaker
And at the end of the day,
00:30:32
Speaker
about 500 patients for 500 patients actually receive peripheral vasopressors between the two arms.
00:30:39
Speaker
We also follow that specifically for any problems or complications or adverse events.
00:30:46
Speaker
And we can probably comment on that a little bit more ahead, because that was something that when you presented the findings at the Society of Critical Care Medicine annual meeting earlier this year, it surprised me not necessarily that it's a discussion topic in a lot of places, but it
00:31:06
Speaker
when you talked about 500 patients that received, that you actually had studied within the Clover study that received peripheral vasopressors, that was very interesting.
00:31:15
Speaker
So we'll come back to that.
00:31:17
Speaker
And I think it's a great example of how when we study, when we take these enormous efforts to do these large clinical trials, even if the hypothesis is considered a negative finding, there's a lot that we can learn about how to improve and advance care
00:31:36
Speaker
that comes from these efforts.
00:31:38
Speaker
And we'll get back to that.
00:31:39
Speaker
But thanks for sharing that.
00:31:41
Speaker
Quick question in terms of, and I just also want to point out that the protocols obviously are shared in the manuscript and they're beautiful.
00:31:50
Speaker
I mean, very concise, but I'm sure that getting to that level of clearness required a lot of discussion and back and forth.
00:32:01
Speaker
Yeah, it did.
00:32:02
Speaker
It was a lot of discussion, a lot of thoughtful discussion.
00:32:05
Speaker
And probably the most informative was there was clearly clinicians who wore the hat of a liberal clinician and clearly those who had a bias towards a restrictive.
00:32:18
Speaker
And really what we tried to do is we wanted the restrictive clinicians to feel good about the restrictive protocol and the liberal clinicians to feel about good about the liberal protocol.
00:32:28
Speaker
Yeah.
00:32:29
Speaker
And so there was discussions and tips and, you know, we kind of put it back and forth and we kind of hammered it out until we got reasonable consensus between the groups.
00:32:39
Speaker
Excellent.
00:32:40
Speaker
So tell us what happened.
00:32:42
Speaker
First, why don't we go over how long was this protocol implemented and why and what happened during that time of the protocol implementation?
00:32:53
Speaker
Were the groups different and what happened throughout the trial?
00:32:56
Speaker
Sure.
00:32:57
Speaker
So the, in the liberal group, it was up to 24 hours or, uh, once you hit the five liter mark, then you went to usual care.
00:33:06
Speaker
Um, we were very specific cause as you remember the rivers was six hours and we felt that we really wanted to cross that because it didn't make sense.
00:33:17
Speaker
We needed, you know, the first resuscitation period usually exceeds six hours.
00:33:21
Speaker
And so that's why we bridge it up to 24 in the restrictive
00:33:26
Speaker
hours and then went to usual care.
00:33:29
Speaker
And so that was, that's the protocol period.
00:33:33
Speaker
The groups were definitely different in terms of fluids.
00:33:37
Speaker
There's about a two liter difference at the end of the day.
00:33:41
Speaker
But when you look at it,
00:33:44
Speaker
It was a lot of the real action happened in the first six hours, in fact.
00:33:48
Speaker
So if you look at the six hour period, it was a median of 500 CC's compared to in the restrictive group compared to 2,300 in the liberal group.
00:33:57
Speaker
And then over 24 hours, it was 1267 CC's versus 3,400.
00:34:00
Speaker
And the difference was, um, 2.1 liters.
00:34:06
Speaker
And then on the vasopressor side, there was more prevalent use of vasopressors in the restrictive group.
00:34:13
Speaker
It was 59% to 37% through 20%, 21.7% difference.
00:34:18
Speaker
Whereas time to randomization was earlier in the restrictive group, 1.8 hours versus 3.2 hours.
00:34:25
Speaker
And vasopressors were used longer than restrictive group, 9.6 hours versus 5.4 hours.
00:34:30
Speaker
So looking at more fluids in the liberal group, earlier, more prevalent and longer use of vasopressors in the restrictive group, we felt that we had done a, we performed a clinical trial and there was two different groups that were tested and the protocols were followed enough to achieve
00:34:50
Speaker
And I know that you mentioned that also in the protocol adherence, we're talking about 96% and 97%, I think.
00:34:59
Speaker
So very well documented, at least, what you could measure, which I think is also very important and reflects the point that you made earlier that these were actual protocols to be used at the bedside and clinically relevant.
00:35:13
Speaker
That's correct.
00:35:15
Speaker
So what did the results show?
00:35:18
Speaker
So as far as our primary outcome of mortality, no difference between the groups.
00:35:24
Speaker
In the liberal group, it was 14.9% mortality compared to 14.0% in the restrictive group, and the difference was not statistically significant, a P of 0.61.
00:35:38
Speaker
And then when we looked across all of our secondary outcomes, those were also no difference between the groups.
00:35:45
Speaker
So at the end of the day, it was two approaches to resuscitation in patients who were identified on average within an hour.
00:35:55
Speaker
And when we paid close attention to them for at least 24 hours in the protocol period or afterwards, and it led to the same outcomes.
00:36:04
Speaker
Absolutely.
00:36:05
Speaker
And I think worth mentioning for our audience, at the end, you had a little bit over 1,500 patients, but the trial was terminated early, right?
00:36:16
Speaker
Correct.
00:36:16
Speaker
So there was pre-planned interim analyses at one-third of the way through the trial, two-thirds of the way through the trial, and then you would complete the trial.
00:36:27
Speaker
And at two-thirds, the DSMB looked at the data and felt that there was no difference between the groups and that enrolling additional patients was not going to change that.
00:36:40
Speaker
Also of note, there was a no diff.
00:36:43
Speaker
We had secondary outcomes such as organ failure, free days.
00:36:48
Speaker
Um, and there, no difference there than three days, no difference there, new intubation, no different serious adverse events, no difference.
00:36:56
Speaker
So really in addition to not hitting the primary outcome, two thirds of the way through everything across the board looked very similar.
00:37:04
Speaker
So they just felt that it was terminated due to fees due to, um,
00:37:09
Speaker
essentially due to futility, because they felt that enrolling additional patients was unlikely to change the
00:37:18
Speaker
So one aspect about this trial that for me is fascinating as a clinician who is part of a very large community practice of critical care is that the Hawthorne effect, right?
00:37:31
Speaker
And the point that you have a very elegant protocol for either restrictive or liberal, that I'm sure because people were aware they're part of a trial, right?
00:37:43
Speaker
was probably taken very seriously.
00:37:46
Speaker
And I would imagine that where you're a liberal camp or restrictive camp in the community or in the wild type care community or academic, not every patient probably gets the same level of attention in terms of fulfilling this protocol.
00:38:04
Speaker
And that itself, I think, is something probably very, very important and valuable for clinical care.
00:38:10
Speaker
Any thoughts on that, Nate?
00:38:12
Speaker
Yeah, no, I completely agree.
00:38:13
Speaker
I mean, this is, you have to remember that in order to interpret these results, it's in the backdrop of a patient who's identified early on average one hour from being, having a blood pressure less than a hundred after liter fluids, who, um, receives in the liberal group care that looks like, um,
00:38:35
Speaker
several liters of fluid within the first few hours and an additional fluid or in restrictive that looks like vasopressors given reasonably early if they're indicated.
00:38:47
Speaker
And so it's really at the end of the day, what I, what I took from process promise and arise was that goal directed therapy was no better than, um, than no goal directed therapy, but in the backdrop of identifying the
00:39:07
Speaker
nervous resuscitation.
00:39:08
Speaker
And I think that carries over here, which is you still need compulsive care at the bedside.
00:39:13
Speaker
It's just compulsive care.
00:39:16
Speaker
In the setting of compulsive care, it doesn't matter if you reach for fluids first or vasopressors first.
00:39:21
Speaker
And I have to say for me personally, so I entered the
00:39:26
Speaker
I would say it's fair to say that I entered the trial as a clinician who typically used a liberal, in general, a liberal approach to resuscitation that was very fluid predominant.
00:39:38
Speaker
However, there were certainly patients that I either helped with as part of the research team or helped with just because they were my own patients involved in the trial.
00:39:48
Speaker
And for those patients, when they were randomized to restrictive, what I realized very early on in the trial is for most patients, I can make them normal intensive with either approach.
00:39:59
Speaker
Most patients, their blood pressure would correct whether I use a fluid centric approach or a vasopressor centric approach.
00:40:07
Speaker
What I didn't know during the trial was if one approach or the other led to better outcomes from the patient's perspective.
00:40:13
Speaker
And I think now that the trial is complete, what I've learned is both are reasonable alternatives if you pay attention to all parts of the care.
00:40:22
Speaker
So in terms of future research questions with post-clovers, are there specific areas that the group is interested in, or are we going to wait and see trials that are ongoing and try to put all that together?
00:40:39
Speaker
Where do you think we go from here?
00:40:41
Speaker
Yeah, no, it's a great question.
00:40:43
Speaker
So there's still, we have, there's a couple trials that are ongoing now as secondary parts of clover.
00:40:50
Speaker
There's one that myself and Eric Schmidt from Mass General are doing, which is our hypothesis is that glycocalyx degradation is important.
00:41:00
Speaker
And essentially patients who have glycocalyx, the first hypothesis is that
00:41:07
Speaker
a fluid liberal approach will lead to increased glycocalyx degradation.
00:41:12
Speaker
This is a hypothesis we're testing, so we're doing biomarkers mass spec.
00:41:17
Speaker
And the second hypothesis is glycocalyx degradation is important in relation to outcomes.
00:41:23
Speaker
And the third and perhaps more important one is whether there's patients with certain profiles of glycocalyx degradation who may preferentially benefit from one arm or the other.
00:41:32
Speaker
So are there subgroups of patients who are going to do better with fluids?
00:41:36
Speaker
versus are there other subgroups of patients who will do better with a restrictive approach?
00:41:41
Speaker
And then in that germane, we have some echo-based studies going on that Sam Brown is leading.
00:41:48
Speaker
And then just in general, I think there's an, we didn't really look for two, there was no difference in the subgroups that we looked at, but it's possible that other approaches, certainly more advanced molecular phenotyping approaches may identify certain populations that may benefit from
00:42:05
Speaker
one approach or the other.
00:42:07
Speaker
Interesting.
00:42:08
Speaker
And I think that ultimately, obviously, we always talk about personalized medicine, but getting there is a lot more difficult than talking about it.
00:42:17
Speaker
But that would be, I guess, the direction, which makes sense, right?
00:42:20
Speaker
We have this very heterogeneous syndrome.
00:42:24
Speaker
And to believe that one simple size fits all is probably not the right route.
00:42:34
Speaker
So as we move towards a closing, Nate, I wanted to touch one more time on that peripheral vasopressor discussion because, as you mentioned, this is something that is a topic of discussion in many ICUs.
00:42:48
Speaker
Some have been more progressive in embracing the use of vasopressors administered through peripheral Lyme.
00:42:58
Speaker
I think with the right precautions, it seems to be something that can be done.
00:43:03
Speaker
But like a lot of our discussions, we have to be careful that the pendulum doesn't swing too far because there are benefits and there are some patients in whom a timely central line probably is important.
00:43:14
Speaker
And I just think that obviously that was not the primary hypothesis we're testing, but I don't believe that we have another group of 500 patients who had peripherally infused vasopressors within the context of a clinical trial where we have some data.
00:43:32
Speaker
Could you comment on this a little bit more, what you found and what is your personal take?
00:43:39
Speaker
Yeah, so it was 50 patients, 500 patients,
00:43:42
Speaker
received in one arm or the other peripheral vasopressors.
00:43:47
Speaker
And then there was three reported incidents of adverse events.
00:43:52
Speaker
It was three episodes of extravasation and all three were self-limited and didn't lead to any clinical consequences.
00:43:59
Speaker
So in this sample of 500 patients, it looks like a reasonably safe practice.
00:44:04
Speaker
You know, I think that includes trying to make sure just general common sense approaches like
00:44:13
Speaker
line that's tenuous and hanging halfway out of the arm but for in general if you have a good lining and use this approach it lets you get the vasopressors in earlier the other thing that we saw from the trial this is from experience is that a lot of times we'd start vasopressors and then the and also looking at the data and then the vasopressors 12 hours later would just come off
00:44:38
Speaker
They would just not be needed anymore.
00:44:40
Speaker
So a lot of the vasopressors, or there's a subset of patients who needed hours worth of vasopressors, or who received hours worth of vasopressors, and then would become normotensive and drift up, and it spared those patients in the central line.
00:44:56
Speaker
Certainly, there was more central lines placed in the restrictive group than in the liberal group.
00:45:01
Speaker
The other thing to comment on as well is there was about, I think it was 80% more patients in the restrictive group went to the ICU compared to the liberal group, presumptively because of the earlier and more prominent use of vasopressors.
00:45:17
Speaker
But one could say it's a secondary analysis, but one could say it's a little bit less ICU utilization in the liberal group.
00:45:26
Speaker
Or another way to operationalize it is the practice of giving fluids to see if you can get to normal tension without vasopressors does not appear to have had negative effects in this study.
00:45:38
Speaker
Interesting.
00:45:39
Speaker
So as we close, Nate, obviously this is a topic that has been part of your research interest for some years now, and this is not the first study, obviously, that you've been involved or the last, but you're also a practicing clinician.
00:45:54
Speaker
So my departing question on this topic is if you could share with us any lessons for the bedside.
00:46:01
Speaker
So how do you approach resuscitation with fluid invasive suppressors in your septic-induced hypotension patients?
00:46:08
Speaker
and any practical advice you want to share with our clinicians?
00:46:12
Speaker
Yeah, I'd say it's still compulsive care at the bedside.
00:46:15
Speaker
It's still treat, assess the response, reassess the patient, and then treat again.
00:46:22
Speaker
It's just that I've now included, I think it's fair to include vasopressors, in particular peripheral vasopressors, into the armamentarium.
00:46:33
Speaker
It's changed my practice a bit in that I'll reach for vasopressors a little bit earlier, knowing that
00:46:40
Speaker
fluids and then in the bigger picture I've been kind of squabbling over fluids and vasopressors personally in the research world for a decade or two and maybe if we're going to make real gains or strides in improvement towards patient outcomes we have to look towards other therapies novel therapies
00:47:05
Speaker
perhaps not going to be, or I think it's less promising that it's going to be through the right balance of fluids or these oppressors.
00:47:12
Speaker
Absolutely.
00:47:13
Speaker
So we like to close the podcast, Nate, with some questions that are unrelated to the clinical topic.
00:47:20
Speaker
Would that be okay?
00:47:21
Speaker
Yeah, sure.
00:47:23
Speaker
The first question relates to books.
00:47:24
Speaker
And I was wondering if there's a book or any books that have influenced you very deeply or that you have gifted frequently to friends.
00:47:34
Speaker
Yeah.
00:47:34
Speaker
So there's a book called, there's a little bit of a story behind it.
00:47:37
Speaker
There's a book called extreme ownership.
00:47:40
Speaker
It's by Jocko willing and Lee founded and there are two Navy seals and it's kind of directed towards the business world where they take lessons from their Navy seal training and battle experience and say how that goes towards good team dynamics or goal directed operations or orientation in the business world.
00:47:59
Speaker
But I find that it applies to the medical world and maybe life in general.
00:48:03
Speaker
And it just,
00:48:04
Speaker
uses some of those SEAL training techniques, defining an objective, making sure the team knows the objective, good communication, et cetera.
00:48:13
Speaker
And I found that to be just a useful book.
00:48:16
Speaker
And so that's my answer.
00:48:19
Speaker
Perfect.
00:48:20
Speaker
And I've gifted that more than anything.
00:48:21
Speaker
Yeah, and we will definitely link that.
00:48:23
Speaker
It's an excellent book.
00:48:24
Speaker
And for those of our audience who are active on Twitter, look up Joko Wilkins, and you can be shamed every morning around 4 a.m.
00:48:34
Speaker
when he starts his workout, right?
00:48:36
Speaker
Yeah.
00:48:38
Speaker
Perfect.
00:48:40
Speaker
The second question is something that you believe to be true in medicine or life that most other people don't believe or don't act like they believe.
00:48:48
Speaker
I don't know if most people don't believe it, but at the end of the day, I feel like simple observation and common sense is perhaps the key skill at the bedside.
00:48:58
Speaker
More important than complex readouts or sophisticated analysis, but
00:49:02
Speaker
really taking a step back, seeing the forest through the trees and, and just some of these simple things that are right there staring you in the face that you just need to receive and act on, um, is maybe the most important.
00:49:16
Speaker
And I think it is very powerful.
00:49:18
Speaker
And I do believe that if people agree with that statement, it's not what we see on a regular basis because one of my observations has always been that common sense is quite uncommon.
00:49:31
Speaker
Yes, exactly.
00:49:34
Speaker
Perfect.
00:49:35
Speaker
And the last question, Nate, relates to what would you want every intensivist and APP listening to us to know could be a quote, a fact, or just a thought on what we discussed today?
00:49:46
Speaker
So I'll respond in two.
00:49:47
Speaker
One is there's a quote.
00:49:48
Speaker
I think I actually heard it first from Wes Ely.
00:49:51
Speaker
And it's less attentive, but just more in general in the research world, which is the reason to do research is to help patients that you'll never meet.
00:50:00
Speaker
To see if you can find some sort of truth or knowledge or clinical tip or fact that's not going to be used on your patients, but that you can share that will help other patients.
00:50:11
Speaker
And the second one kind of related to our simple observation, but just compulsive care and kindness at the end of the day is perhaps most important.
00:50:19
Speaker
And paying attention to the details for the patient and then also the needs of the patient families are, as we all know,
00:50:29
Speaker
Perfect.
00:50:29
Speaker
And I think this is a very good place to stop.
00:50:32
Speaker
I want to thank you first for the tremendous effort that the whole Clovers team has put forward.
00:50:38
Speaker
I think people sometimes don't appreciate how much effort these trials take and how much involvement the clinicians, the investigators, and everybody who participates has in this.
00:50:54
Speaker
And it's very important for us to advance, obviously, the care we provide.
00:50:59
Speaker
Also want to thank you for being so generous with your time and expertise today.
00:51:03
Speaker
And definitely hope to have you back on the podcast to discuss more of your research, but also more of these clinical topics.
00:51:10
Speaker
My pleasure.
00:51:10
Speaker
Thanks for having me.
00:51:11
Speaker
And I also want to echo that this trial was a real team approach between Clover's committee, the 60 hospitals involved, all the nurses, clinicians, research assistants.
00:51:23
Speaker
It was really a tremendous effort all around.
00:51:27
Speaker
Thanks, Nate.
00:51:27
Speaker
Thanks for having me.
00:51:28
Speaker
Take care.
00:51:31
Speaker
Thank you for listening to Critical Matters, a sound podcast.
00:51:34
Speaker
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00:51:40
Speaker
Sound's transforming the way critical care is provided in hospitals across the country.
00:51:45
Speaker
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